Methods and apparatus for the enhanced delivery of physiologic agents to tissue surfaces

ABSTRACT

Apparatus and methods deliver physiologically active agents in the presence of adjuvant gases. The adjuvant gases can enhance the effectiveness of the drug, lower the dosage of drug or concentration of drug necessary to achieve a therapeutic result, or both. Exemplary adjuvant gases include carbon dioxide, nitric oxide, nitrous oxide, and dilute acid gases.

This application is a continuation of U.S. application Ser. No.11/340,410, filed Jan. 25, 2006; which is a continuation-in-part of U.S.application Ser. No. 11/192,852, filed Jul. 29, 2005; which is acontinuation-in-part of U.S. application Ser. No. 09/708,186, filed Nov.7, 2000, now U.S. Pat. No. 6,959,708, issued Nov. 1, 2005; which claimsthe benefit of U.S. Provisional Patent Application Nos. 60/164,125,filed Nov. 8, 1999 and 60/185,495, filed Feb. 28, 2000. The contents ofthe above-identified applications are incorporated herein by referencein their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to drug delivery. More particularly, thepresent invention relates to methods and apparatus for deliveringphysiologically active agents to mucosal and other tissue surfaces inthe presence of adjuvant gases.

Drug delivery to mucosal surfaces, such as the mucosa of the nose, iswell known. While in some cases drugs delivered to the nose and othermucosal surfaces are intended to have local effect, more often suchtransmucosal drug delivery is intended for systemic administration. Ineither case, penetration of the drug into or through the mucosa islimited by the ability of the particular drug to pass into or throughthe mucosal cell structure. Such resistance from the mucosal cellstructure can result in slowing of the delivery, the need to use higherdosages of the drug, or in the case of larger molecules, the inabilityto deliver via a nasal or other mucosal route.

For these reasons, it would be desirable to provide improved methods andsystems for transmucosal drug delivery in the nose and other organs. Itwould be desirable if the concentration of drug being delivered could belowered while achieving an equivalent local or systemic physiologiceffect. It would be further desirable if the activity or effectivedelivery of the drug could be enhanced without the need to raise thedosage or drug concentration. At least some of these objectives will bemet by the invention described and claimed hereinbelow.

2. Description of Background Art

Inhalation devices, systems and methods for delivering carbon dioxideand other gases and aerosols to patients, with and without co-deliveryof a drug are described in U.S. Pat. Nos. 3,776,227; 3,513,843;3,974,830; 4,137,914; 4,554,916; 5,262,180; 5,485,827; 5,570,683,6,581,539; and 6,652,479. While some methods and devices provide forco-delivery of a drug and carbon dioxide or other gases, the purpose isusually not potentiation. For example, carbon dioxide may be used as asafe propellant, as shown in Wetterlin, U.S. Pat. No. 4,137,914. Seealso copending application Ser. No. 09/614,389 (Attorney Docket No.020017-000110US); Ser. No. 10/666,947 (Attorney Docket No.020017-000420US); and Ser. No. 10/666,562 (Attorney Docket No.020017-000430US), the full disclosures of which are incorporated hereinby reference.

Additional background art may be found in the following references:Guyton A C, Hall J E. Textbook of Medical Physiology. Ninth Ed., W.B.Saunders Co., Philadelphia, 1996; Tang A, Rayner M, Nadel J. “Effect ofCO₂ on serotonin-induced contraction of isolated smooth muscle. ClinResearch 20:243, 1972; Qi S, Yang Z, He B. An experiment study ofreversed pulmonary hypertension with inhaled nitric oxide on smokeinhalation injury. Chung Hua Wai Ko Tsa Chih 35(1):56-8, January 1997;Loh E, Lankford E B, Polidori D J, Doering-Lubit E B, Hanson C W, AckerM A. Cardiovascular effects of inhaled nitric oxide in a canine model ofcardiomyopathy. Ann Thorac Surg 67(5): 13 80-5, May 1999; Pagano D,Townend J N, Horton R, Smith C, Clutton-Brock T, Bonser R S. Acomparison of inhaled nitric oxide with intravenous vasodilators in theassessment of pulmonary haemodynamics prior to cardiac transplantation.Eur J Cardiothorac Surg 10(12):1120-6, 1996; and Sterling G, et al.Effect of CO2 and pH on bronchoconstriction caused by serotonin vs.acetylcholine. J. of Appl. Physiology, vol. 22, 1972.

SUMMARY OF THE INVENTION

The present invention provides methods and systems for deliveringphysiologically active agents to tissue. The methods rely on contactinga tissue surface, typically a mucosal tissue surface, with thephysiologically active agent while simultaneously and/or sequentially(either before or after) suffusing the same tissue surface with anadjuvant gas which promotes the uptake of the agent by the tissue and/orwhich promotes an activity of the agent. Mucosal surfaces targeted fordrug delivery by the methods and apparatus of the present inventioninclude the nasal mucosal surface, oral mucosal surfaces, ocular mucosalsurfaces, auricular mucosal surfaces, and the like. The adjuvant gas maybe any vasoactive, myoactive, or neuroactive gas or vapor which iscapable of enhancing the efficacy of the agent being delivered and/orwhich is capable of reducing the dosage or concentration of agent beingdelivered while achieving an activity equivalent to a higher dosageand/or concentration. Preferred adjuvant gases include carbon dioxide,nitric oxide, nitrous oxide, and dilute acid gases, such as dilutehydrochloric acid, hydrofluoric acid, and the like. Particularlypreferred are carbon dioxide gases having a relatively highconcentration, typically greater than 10% by volume, usually greaterthan 20% by volume, and preferably greater than 25% by volume and oftenbeing as great as 80% by volume, 90% by volume, and in many instancesbeing substantially pure. The adjuvant gases may be used in combinationsof two or more adjuvant gases and/or may be combined withphysiologically inert gases such as nitrogen, to control concentrationof the active gases.

The physiologically active agent will be in a form which is capable ofbeing delivered to the mucosal or other tissue surface, usually being inthe form of a gas, vapor, liquid, mist, or powder. In certain instances,however, the drug can be in the form of a pill or other conventionalsolid dosage form which may be placed on the mucosal or other surface,e.g., beneath the tongue when the oral cavity is to be suffused with theadjuvant gas. Physiologically active agents which may be deliveredinclude drugs selected from the group consisting of nitroglycerin,triptans, imidazopyridines (such as zolpidem available under the brandname Ambein®), 5-HT3 antagonists (such as ondansetron available underthe brand name Zofran®), epinephrine, angiotensin II, atrophine,apomorphine, opioids, and the like.

Systems according to the present invention for deliveringphysiologically active substances to a mucosal surface comprise a sourceof an adjuvant gas and a source of the physiologically active substance,typically in fluid or other deliverable form. The systems may comprisesome mechanism, structure, or the like, for delivering both the adjuvantgas and the physiologically active substance to the mucosal surface.Usually, the delivering structure will comprise a hand-held dispenser,for example where the dispenser includes a pressurized source of theadjuvant gas and a valve assembly for releasing the gas at a controlledflow rate, typically in the range from 0.5 cc/sec to 20 cc/sec in thecase of high concentration of carbon dioxide. The physiologically activesubstance may be dissolved or suspended in the pressurized adjuvant gasfor simultaneous delivery. Alternatively, the physiologically activesubstance may be delivered from a separate receptacle, either throughthe same or a different delivery path. Often, the adjuvant gas and thephysiological gas, even when stored in separate receptacles, will bedelivered through a common conduit and nozzle to allow for bothsimultaneous and sequential delivery. The exemplary adjuvant gases andphysiologically active agents incorporated into these systems are thesame as those set forth above with respect to the method.

The co-application of a drug with the adjuvant gas can be performed inat least three different ways. First, the drug and gas can be appliedtogether locally by co-infusion and transmucosal co-absorption nasally,orally, and/or via the eye or ear. The form of the drug, of course,would need to be suitable for such infusion, for example, a fine powderor liquid. If the combination of the drug and gas is applied nasally ororally for local transmucosal absorption, the individual wouldpreferably substantially inhibit passage of the drug and gas into hislungs and trachea by limiting inhalation of the gas and drug. Second,the drug and gas may be applied separately. The drug will be applied toinfuse a nostril or nostrils, mouth, eye or ear or other body cavityhaving a mucosal surface with the gas before, during or afterapplication of the drug.

As an example of the first method, a drug previously infused into theoral cavity, mouth, eyes, or ears by entraining with air, e.g., as anaerosol, powder, or spray, can be applied according to the presentinvention by entraining with CO₂, e.g., through aspiration of adrug-containing liquid or powder by CO₂. In particular, the action ofdrugs developed and presently used for relieving respiratory andheadache symptoms may be improved by their co-infusion with CO₂, NO, orother adjuvant gases identified herein. The vasodilation which may beinduced by CO₂ or NO may improve the speed and extent of absorption anddistribution of the drug in the tissue in which it is co-absorbed withCO₂ or NO. This is beneficial through more rapid relief being obtained,and/or through reduction in the quantity of drug required to obtain therelief. Reduction in the required quantity of drug reduces the cost oftreatment per dose and particularly reduces the side effects of suchdrugs, which are severe restrictions to their present use.

With respect to the second method, a particular benefit ofco-application of such drugs with CO₂ or other adjuvant gases is that,in addition to the reduction of the total amount of drug required, theeffect of the drug can be controlled or “modulated” in the course of itsaction after application. Infusion of CO₂ prior to drug application canincrease the effectiveness and reduce the required quantity of the drug.Alternatively, infusion of CO₂ after application of a drug can enhancethe effect of the drug at a controlled rate; i.e., if a more rapid ormore intense effect of the drug is desired, CO₂ can be infused at therate required to obtain the desired degree of enhancement. A particularadvantage of such control is that the drug enhancement effect can beabruptly terminated, by ceasing CO₂ infusion, at the optimum level ofbeneficial drug effect that minimizes side or overdose effects. Also,since CO₂ is rapidly eliminated from the body via the bloodstream andrespiration, the enhancement is reversible after CO₂ application isceased, allowing continuous chronic adjustment of the drug effect.

An example of the beneficial regulation of the effect of a powerful drugby CO₂ inhalation or infusion is the co-application of CO₂ andnitroglycerin for the relief of acute angina and during onset of a heartattack (myocardial infarction). Nitroglycerin is a powerful vasodilator.Ordinarily persons suffering from angina or from symptoms of heartattack place a nitroglycerin tablet under their tongue (transmucosaldelivery). If this is not adequate to relieve the symptoms within threeminutes, another tablet is similarly ingested. After another threeminutes, if relief is not obtained, this process is again repeated. Ifthe symptoms then persist, a person should be taken immediately to ahospital for emergency treatment. Some persons are extremely sensitiveto the side effects of nitroglycerin however, including severe bloodpressure reduction that can result in dizziness and fainting, especiallyafter ingesting the second tablet, at a time when good judgment anddeliberate corrective action are required. A few minutes of delay can becrucial after the onset of a heart attack. With co-application, CO₂ canbe infused after the first tablet to rapidly enhance and sustain itseffects, possibly reducing the need for subsequent tablets. The effectsof a second tablet of nitroglycerin can be initiated gradually andreversibly with CO₂ application to maintain and extend the optimumdegree of pain relief without severe blood pressure reduction.

In all three methods cited only one physiologically active or otheradjuvant gas is used; however, physiologically active gases may be usedtogether, with or without drugs. For example, CO₂ has been found torelax both central and peripheral airways in asthmatic adults (Qi et al.(1997) supra). Similarly, in both in vivo and clinical tests, inhaledlow dose NO has been found to be as effective as sodium nitroprussideand prostacyclin in reducing transpulmonary gradient and pulmonaryvascular resistance, and is highly pulmonary vasoselective (Sterling etal., (1972) supra). NO has also been found to reverse pulmonaryhypertension (Loh et al. (1999) and Pagano et al. (1996), supra).Therefore, NO and CO₂ can be co-applied to potentiate their respectiveactions or otherwise interact.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an exemplary co-infusion device, illustrating thecharge/dose and dose rate adjustment features.

FIG. 2 is a schematic illustration of a delivery system incorporatingseparate receptacles for the adjuvant and the physiologically activeagent, where the receptacles are joined through valves into a commondelivery conduit.

FIGS. 3A-3E show application of the adjuvant gas optionally incombination with the physiologically active agent to the nose, mouth,both nostrils, eye, and ear, using a gas dispenser according to thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

An exemplary carbon dioxide dispenser 100 comprising a carbon dioxidecartridge 101 is illustrated in FIG. 1. The embodiment of FIG. 1 isdescribed in greater detail in parent application Ser. No. 09/708,186,now U.S. Pat. No. 6,959,708, the full disclosure of which has previouslybeen incorporated herein by reference. A user delivers a dose of carbondioxide (optionally carrying the physiologically active agent to bedelivered) by applying the top of the dispenser 608 to the user's noseor mouth and pushing a button 600 which releases an internal mechanismto allow the CO₂ to flow from the top of the dispenser 608. The internalmechanism will lower the pressure of CO₂ in the cartridge and willcontrol the flow rate within suitable ranges, typically from 2 to 10cc/sec. The flow rate may be maintained for a suitable time period,typically at least 2 seconds when suffusing the nasal and sinuspassages. The device is cocked by rotation as shown by arrow 602 andpushing the button 600 to deliver the dose by an automaticcounter-rotation. The user may select the specific carbon dioxide flowrate by setting at a set screw through aperture 609.

The hand-held dispenser 100 of FIG. 1 may be used to deliver any of theadjuvant gases in accordance with the principles of the presentinvention. The adjuvant gases may be delivered with or without thephysiologically active agent incorporated in the canister 101. In caseswhere the adjuvant gas is to be delivered by itself, at some suitableconcentration, the physiologically active agent will have to bedelivered to the target mucosal or other tissue surface in some othermanner. The physiologically active agent, for example, could bedelivered by separate suffusion or infusion, by placing a liquid,powder, or the like over the tissue surface, by introducing a vapor,mist, or the like using conventional drug delivery vapor sources andmisters, or the like. In some instances, such as the delivery ofnitroglycerin, it would be possible to simply place a solid dosage format the mucosal surface through which the drug is to be delivered. Theadjuvant gas can be delivered before, during, and/or after any of thesteps taken to deliver the physiologically active agent.

FIG. 2 is a schematic illustration showing a system for simultaneous orsequential delivery of the adjuvant gas and physiologically activeagent. The adjuvant gas is held in a separate cartridge or othercontainer 202 while the physiologically active agent is held in acartridge or other container 204. Both the gas and the physiologicallyactive agent will be in a gaseous, vapor, mist, or other flowable formwhich permits them to pass through associated valves 206 and 208respectively, and thereafter through a conduit 210 which receives flowfrom both valves. The valves will be suitable for controlling both flowrate and pressure of the adjuvant gas and the physiologically activeagent. It will be appreciated that more complex delivery systems can beprovided including flow rate measurement, feedback control, temperaturecontrol, timers, and the like.

Referring now to FIGS. 3A to 3E, a variety of ways for effecting mucosalinfusion with the adjuvant gas, optionally combined with thephysiologically active agent, are illustrated. The adjuvant gas ispreferably infused at a flow rate in a range from 0.5 cc/sec-20 cc/sec,depending on the tolerance of the individual being treated. In someinstances, the selected drug or other physiologically active agent canbe delivered separately by suffusion, infusion, misting, the applicationof powder, or the like. As shown in FIG. 3A-B, the individual P theninfuses oral and nasal mucous membranes by placing the source of lowflow rate CO₂ or other appropriately physiologically active gas or vaporin or around a facial orifice, such as the mouth or nostril, whilesubstantially inhibiting the flow of the CO₂ into the trachea and lungsby limiting inhalation of the CO₂. If the mouth is infused the gas isallowed to exit from the nostrils. Alternatively, one or both nostrilsmay be infused either by using the dispenser head shown in FIG. 3B or byuse of a cup or similar device that covers both nostrils as shown inFIG. 3E. The gas is allowed to flow from a remaining open orifice, i.e.,either the mouth, the uninfused nostril, or both as appropriate.Completely holding the breath is not necessary to substantially preventinhalation of the CO₂. With practice, it is possible for the individualto breathe through an uninfused orifice: for example, if one nostril isinfused and the gas is allowed to exit through the other nostril, it ispossible for the individual to breathe through the mouth withoutsubstantial inhalation of the infused gas. The eye or eyes may also beinfused using a cup as shown in FIG. 3C or merely by holding a hand overthe eye and releasing the gas between the hand and the eye. Persons ofordinary skill in the art will appreciate that a double cup could bedeveloped to infuse both eyes simultaneously, and similarly appropriateheads could be developed to infuse the mouth and one nostril. The ear orears may also be infused as shown in FIG. 3D. Note that a similarprocess may be used with the first embodiment to infuse a mixture of adrug and gas into various facial orifices.

Infusion can be continued to the limit of tolerance or until the desiredpotentiation effect is realized. Since most individuals develop atemporary increased tolerance after extended applications or repeatedapplications, it may be possible and desirable to increase the durationof additional infusions after a few applications when all applicationsoccur within a short time of each other, i.e., approximately 1 to 20minutes between each application.

While the above is a complete description of the preferred embodimentsof the invention, various alternatives, modifications, and equivalentsmay be used. Therefore, the above description should not be taken aslimiting the scope of the invention which is defined by the appendedclaims.

1. A method for delivering physiologically active agents to tissue, saidmethod comprising: contacting a tissue surface with a physiologicallyactive agent; and suffusing the tissue surface with an adjuvant gaswhich promotes uptake of the agent by the tissue or vascular circulationand/or which promotes an activity of the agent.
 2. The method accordingto claim 1, wherein at least a portion of the adjuvant gas is suffusedsimultaneously with contacting of at least a portion of the agent. 3.The method according to claim 1, wherein at least a portion of theadjuvant gas is suffused prior to contacting the agent.
 4. The methodaccording to claim 1, wherein at least a portion of the agent issuffused prior to contacting the adjuvant gas.
 5. The method accordingto claim 1, wherein contacting comprises placing a solid, powder, orliquid form of the agent on or over the tissue surface.
 6. The methodaccording to claim 1, wherein contacting comprises suffusing thephysiologically active agent in a gaseous, vapor, mist, or powder form.7. The method according to claim 1, wherein the adjuvant gas is selectedfrom the group consisting of carbon dioxide, nitric oxide, nitrousoxide, and dilute acid gases.
 8. The method according to claim 1,wherein the physiologically active agent comprises at least one drugselected from the group consisting of nitroglycerin, triptans,imidazopyridines, 5-HT3 antagonists, epinephrine, angiotensin II,atrophine, apomorphine, and opioids.
 9. The method according to claim 1,wherein the tissue surface comprises a mucosal surface.
 10. The methodaccording to claim 1, wherein the tissue surface is a nasal surface, anoral surface, an ocular tissue surface, or an auricular tissue surface.11. A system for infusing a mucosal surface with a physiologicallyactive substance, said system comprising: a source of an adjuvant gas; asource of the physiologically active substance in a fluid form; andmeans for delivering both the adjuvant gas and the physiologicallyactive substance to the mucosal surface.
 12. The system according toclaim 11, wherein the delivering means comprises a hand-held dispenser.13. The system according to claim 12, wherein the hand-held dispensercomprises a receptacle of pressurized adjuvant gas and a valve assemblyfor releasing the gas at a controlled flow rate in the range from 0.5cc/sec to 20 cc/sec.
 14. The system according to claim 13, wherein thephysiologically active substance is dissolved or suspended in thepressurized adjuvant gas.
 15. The system according to claim 11, whereinthe source of adjuvant gas comprises a first receptacle and the sourceof physiologically active substance comprises a second receptacle. 16.The system according to claim 15, wherein the means for delivering boththe adjuvant gas and the physiologically active substance comprises acommon conduit and nozzle for delivering the gas and substancesimultaneously.
 17. The system according to claim 11, wherein the sourceof adjuvant gas comprises a gas selected from the group consisting ofcarbon dioxide, nitric oxide, nitrous oxide, and dilute acid gases. 18.The system according to claim 17, wherein the physiologically activeagent comprises at least one drug selected from the group consisting ofnitroglycerin, triptans, imidazopyridines, 5-HT3 antagonists,epinephrine, angiotensin II, atrophine, apomorphine, and opioids.